Name: 3739-38-6|3-Phenoxybenzoic acid|98%
Brand: Ambeed
SKU: A116615
Price: 9.0 USD
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1
[ 3586-14-9 ]
[ 3739-38-6 ]

Reference： [1]Monatshefte fur Chemie,1936,vol. 67,p. 24,35
[2]Synthetic Communications,1981,vol. 11,p. 439 - 442

2
[ 3739-38-6 ]
[ 3586-15-0 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus pentachloride
	With phosphorus pentachloride
	With thionyl chloride

	With oxalyl dichloride; N,N-dimethyl-formamide In diethyl ether
	With thionyl chloride; N,N-dimethyl-formamide In hexane; chloroform at 60 - 65℃; for 1h;
	With thionyl chloride; N,N-dimethyl-formamide Heating;
	With oxalyl dichloride
	With thionyl chloride; N,N-dimethyl-formamide
	With oxalyl dichloride In dichloromethane at 20℃; for 2h;	46 Add oxalyl chloride (0.20 mL, 2.30 mmol) and 3 drops of DMF to a stirring suspension of 3-phenoxy-benzoic acid (0.247 g, 1.15 mmol) in CH2Cl2 (5.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 3-phenoxy-benzoyl chloride solution to a mixture of rac- N2-methyl-N2-(l-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.200 g, 0.768 mmol) and pyridine (0.06 mL) in CH2Cl2 (5.0 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (aqueous) (3 x 25 mL), dry the organic phase over Na2SC^, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel flash column chromatography (5 x 4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white solid (0.163 g, 46%). mass spectrum (m/e): 457.0 (M+l), 455.0 (M-I). IH NMR (400 MHz, CD3OD): δ 7.72-7.67 (m, 2H), 7.60-7.57 (m, IH), 7.51 (t, J = 7.9 Hz, IH), 7.44-7.38 (m, 2H), 7.35-7.28 (m, 2H), 7.22-7.15 (m, 2H), 7.09-7.05 (m, 2H), 4.18- 4.09 (m, IH), 3.12 (s, 3H), 3.06-3.00 (m, 2H), 2.35 (s, 3H), 2.24 (dt, / = 12.4, 2.4 Hz, 2H), 2.03- 1.92 (m, 2H), 1.87-1.80 (m, 2H).
	With oxalyl dichloride In dichloromethane at 20℃;	7.1 Route 7: Step 1: Acid Chloride Formation (Int 135) 3-Phenoxy-benzoic acid (0.50 g, 0.23 mmol) was dissolved in CH2Cl2. Oxalyl chloride (0.32 g, 0.25 mmol) was added, followed by 1-2 drops of DMF. The reaction was stirred at room temperature, and then concentrated to give the desired acid chloride.
	With thionyl chloride for 6 - 7h; Heating / reflux;	N-(3-PheiioxybenzoyI)-6,7-dhydroxy-l52,354-tetrahydroisoqιiinoIine (If) 3-Phenoxybenzoic acid (131 mg, 0.609 mmol) was suspended in 5 niL thionyl chloride together with a catalytical amount of DMF and refluxed for 6 hours before evaporation. The remaining residue was dissolved in 5 mL DMF and 6,7~dihydroxy- 1,2,3,4-tetrahydroisoquinoline hydrobromide (150 mg, 0.609 mmol) followed by Et3N (171 μL, 1.22 mmol) were added. The resulting mixture was stirred at room temperature for 4 hours and then diluted with 30 ml water followed by extraction with ethyl acetate (325mL). The combined organic phase was dried over MgSO4 and evaporated. Purification with flash chromatography (pet.ether/EtOAc 1/1 → 1/2) yielded 121 mg (54%) of N-(3-phenoxybenzoyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline as an yellowish residue. 1H-NMR (CD3OD) rotameric mixture δ 7.47-7.31 (m, 3H), 7.20-7.05 (m, 3H), 7.05-6.89 (m, 3H), 6.61-6.50 (ma+mi)(br d, 3H) 6.32 (mi)(s, IH), 4.63 (ma)(s, 2H), 4.38 (mi)(s, 2H), 3.91-3.84 (mi)(br, 2H) 3.62-3.51 (ma)(br, 2H), 2.82-2.75 (mi)(br, 2H), 2.75-2.60 (ma)(br, 2H). TLC (pet.ether/EtOAc 1/5) R1 0.74. HRMS (ESI) calc for C22H20NO4 [M+H] 362.1392, found 362.1367; 3-Phenoxybenzoic acid (136 mg, 0.635 mmol) was suspended in 5 mL thionyl chloride together with a catalytical amount of DMF and refluxed for 7 hours before evaporation. The remaining residue was dissolved in 5 mL DMF and 5,8-dichloro-6,7- dihydroxy-l,2,3,4-tetrahydroisoquinoline hydrobromide (200 mg, 0.635 mmol) followed by Et3N (178 μL, 1.27 mmol) were added. The resulting mixture was stirred at room temperature for 8 hours and then diluted with 30 ml water followed by extraction with ethyl acetate (325mL). The combined organic phase was dried over MgSO4 and evaporated. Purification with flash chromatography (pet.ether/EtOAc 1/1 → 1/2) yielded 108 mg (40%) of N-(3-ρhenoxybenzoyl)-5,8-dichloro-6,7-dihydroxy-l,2,3,4- tetrahydroisoquinoline as a pale residue. 1H-NMR (CDCl3) rotameric mixture δ 7.46-7.31 (m, 3H), 7.20-7.01 (m, 6H), 4.76 (ma)(br s, 2H), 4.51 (mi)(br s, 2H), 4.01-3.90 (mi)(br, 2H) 3.68-3.57 (ma)(br, 2H), 2.92-2.81 (mi)(br, 2H), 2.81-2.70 (ma)(br, 2H). TLC (pet.ether/EtOAc 1/5) Rf 0.73. HRMS (ESI) calc for C22Hi7NO4NaCl2 [M+Na] 452.0432, found 452.0370.
	With thionyl chloride In chloroform for 0.5h; Reflux;	General procedure: A mixture of 4a-g (1.85 mmol), thionyl chloride (28 mmol) in chloroform (5 mL) was heated at reflux for 30 minutes. The resulting solution was evaporated under reduced pressure to remove excess thionyl chloride. The residual liquid was added in one portion to a solution of the substituted aniline 5a-u (2.03 mmol), triethylamine (2.31 mmol) and dichloromethane (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2-8 h. It was then treated with 2M HCl, saturated sodium bicarbonate solution, brine, and dried over Na2SO4. The solvent was removed and the resulting solid was purified by flash column chromatography or recrystalization from ethanol to afford the title compounds 6a-v.
	With thionyl chloride at 60 - 80℃;
	With oxalyl dichloride In hexane; N,N-dimethyl-formamide at 20℃; for 1h;
	With thionyl chloride In N,N-dimethyl-formamide at 80℃; for 4h;
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 4h; Reflux;
	With phosphorus pentachloride
	With thionyl chloride In dichloromethane for 4h; Reflux; Inert atmosphere; Schlenk technique;
	With thionyl chloride for 2h; Reflux;
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.5h; Inert atmosphere;
	With thionyl chloride; N,N-dimethyl-formamide at 79℃; for 3h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃;	1 Step 1: Acid Chloride Formation (Int 135) 3 -Phenoxy -benzoic acid (0.50 g, 0.23 mmol) was dissolved in CH2CI2. Oxalyl chloride (0.32 g, 0.25 mmol) was added, followed by 1-2 drops of DMF. The reaction was stirred at room temperature, and then concentrated to give the desired acid chloride.
	With thionyl chloride Reflux;	5.1.18. General procedure 2 for preparation of 64-81, 83-91 General procedure: To a solution of organic acids (1.1 eq) in SOCl2, the reaction wasstirred at reflux, then finished, SOCl2 was removed and 5 mL THFwas added and dropwise to compound 26 (1.0 eq). Mixture wasstirred at r.t overnight. Then solvent was removed, H2O and ethylacetate was added, organic layer was dried by anhydrous Na2SO4and concentrated. Next, to a solution of compounds gained above inethyl acetate, HCl gas was added for 0.5 h, filtered the solid to affordproducts.

Reference： [1]Lock; Kempter [Monatshefte fur Chemie, 1936, vol. 67, p. 24,35]
[2]Koden; Takenaka; Kusabayashi [Molecular Crystals and Liquid Crystals (1969-1991), 1982, vol. 88, # 1-4, p. 137 - 150]
[3]Chen, Grace J.; Chen, Loomis S. [Journal of Fluorine Chemistry, 1996, vol. 79, # 2, p. 125 - 131]
[4]Bishop, Anthony C.; Kung, Chi-Yun; Shah, Kavita; Witucki, Laurie; Shokat, Kevan M.; Liu, Yi [Journal of the American Chemical Society, 1999, vol. 121, # 4, p. 627 - 631]
[5]Shan, Guomin; Wengatz, Ingrid; Stoutamire, Donald W.; Gee, Shirley J.; Hammock, Bruce D. [Chemical Research in Toxicology, 1999, vol. 12, # 11, p. 1033 - 1041]
[6]Nie, Zhe; Perretta, Carin; Lu, Jia; Su, Ying; Margosiak, Stephen; Gajiwala, Ketan S.; Cortez, Joseph; Nikulin, Victor; Yager, Kraig M.; Appelt, Krzysztof; Chu, Shaosong [Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1596 - 1609]
[7]Fujisawa, Takuo; Kurosawa, Motohiro; Katagi, Toshiyuki [Journal of Agricultural and Food Chemistry, 2006, vol. 54, # 17, p. 6286 - 6293]
[8]KrennHrubec, Keris; Marshall, Brett L.; Hedglin, Mark; Verdin, Eric; Ulrich, Scott M. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 10, p. 2874 - 2878]
[9]Current Patent Assignee: ELI LILLY & CO - WO2006/66173, 2006, A2 Location in patent: Page/Page column 63
[10]Current Patent Assignee: AUTOIMMUNE PHARMA - US2007/105866, 2007, A1 Location in patent: Page/Page column 65
[11]Current Patent Assignee: RESPIRATORIUS - WO2008/95852, 2008, A1 Location in patent: Page/Page column 33; 35
[12]Yang, Yinghong; Wang, Zhenling; Yang, Jianzhong; Yang, Tao; Pi, Weiyi; Ang, Wei; Lin, Yanni; Liu, Yuanyuan; Li, Zicheng; Luo, Youfu; Wei, Yuquan [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 954 - 957]
[13]Gao, Xi-Ai; Wang, Xian-Xue; Yan, Hao; Li, Jian; Yan, Ru-Long; Huang, Guo-Sheng [Journal of the Indian Chemical Society, 2013, vol. 90, # 3, p. 381 - 385]
[14]Lourido, Sebastian; Zhang, Chao; Lopez, Michael S.; Tang, Keliang; Barks, Jennifer; Wang, Qiuling; Wildman, Scott A.; Shokat, Kevan M.; Sibley, L. David [Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 3068 - 3077]
[15]Chandnani, Kavita H.; Chandalia, Sampatraj B. [Organic Process Research and Development, 1999, vol. 3, # 6, p. 416 - 424]
[16]Hinsberger, Stefan; Hüsecken, Kristina; Groh, Matthias; Negri, Matthias; Haupenthal, Jörg; Hartmann, Rolf W. [Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8332 - 8338]
[17]Popov; Korchagina; Lobasenko; Pavel'Ev [Russian Journal of General Chemistry, 2014, vol. 84, # 11, p. 2264 - 2266][Zh. Obshch. Khim., 2014, vol. 84, # 11, p. 1906 - 1908,3]
[18]Dai, Huimin; Yu, Chao; Lu, Changsheng; Yan, Hong [European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1255 - 1259]
[19]Eissa, Ibrahim H.; Mohammad, Haroon; Qassem, Omar A.; Younis, Waleed; Abdelghany, Tamer M.; Elshafeey, Ahmed; Abd Rabo Moustafa, Mahmoud M.; Seleem, Mohamed N.; Mayhoub, Abdelrahman S. [European Journal of Medicinal Chemistry, 2017, vol. 130, p. 73 - 85]
[20]Ren, Jie; Li, Yuhang; Ke, Hongwei; Li, Yanting; Yang, Longhe; Yu, Helin; Huang, Rui; Lu, Canzhong; Qiu, Yan [RSC Advances, 2017, vol. 7, # 21, p. 12455 - 12463]
[21]Okita, Toshimasa; Muto, Kei; Yamaguchi, Junichiro [Organic Letters, 2018, vol. 20, # 10, p. 3132 - 3135]
[22]Fournier, Jean-François; Clary, Laurence; Chambon, Sandrine; Dumais, Laurence; Harris, Craig Steven; Millois, Corinne; Pierre, Romain; Talano, Sandrine; Thoreau, Étienne; Aubert, Jérome; Aurelly, Michèle; Bouix-Peter, Claire; Brethon, Anne; Chantalat, Laurent; Christin, Olivier; Comino, Catherine; El-Bazbouz, Ghizlane; Ghilini, Anne-Laurence; Isabet, Tatiana; Lardy, Claude; Luzy, Anne-Pascale; Mathieu, Céline; Mebrouk, Kenny; Orfila, Danielle; Pascau, Jonathan; Reverse, Kevin; Roche, Didier; Rodeschini, Vincent; Hennequin, Laurent François [Journal of Medicinal Chemistry, 2018, vol. 61, # 9, p. 4030 - 4051]
[23]Current Patent Assignee: AUTOIMMUNE PHARMA - WO2018/152405, 2018, A1 Location in patent: Paragraph 00207
[24]Li, Zezhong; Xin, Weixiang; Wang, Qing; Zhu, Mingyan; Zhou, Huchen [European Journal of Medicinal Chemistry, 2021, vol. 217]

3
[ 3586-14-9 ]
[ 127-09-3 ]
[ 53874-67-2 ]
[ 3739-38-6 ]
[ 50789-44-1 ]

Reference： [1]Journal of Organic Chemistry,1987,vol. 52,p. 4925 - 4927

4
[ 3586-14-9 ]
[ 3739-38-6 ]
[ 13826-35-2 ]
[ 39515-51-0 ]

Reference： [1]Australian Journal of Chemistry,1989,vol. 42,p. 1367 - 1373

5
[ 67-56-1 ]
[ 3739-38-6 ]
[ 50789-43-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid
	With sulfuric acid
	With sulfuric acid for 2h; Inert atmosphere; Reflux;

With sulfuric acid at 60℃; for 3h;

18.1 first step:3-phenoxybenzoic acid (1 g, 4.67 mmol) was dissolved in 30 ml of methanol, 3 ml of concentrated sulfuric acid was added, heated at 60 ° C for 3 hours,After the TLC test was finished, the mixture was diluted with water, extracted with EA (50 ml x 3), washed with organic phase, saturated brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give 1.02 g, without purification directly for the next step reaction.

Reference： [1]Nagarapu, Lingaiah; Ravirala, Narender; Akkewar, Dattatray M. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1998, vol. 37, # 12, p. 1254 - 1257]
[2]Jung, Young-Sik; Kang, Tae-Souk; Yoon, Joong-Ho; Joe, Bo-Young; Lim, Hee-Jong; Seong, Churl-Min; Park, Woo-Kyu; Kong, Jae-Yang; Cho, Jungsook; Park, No-Sang [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 18, p. 2599 - 2602]
[3]Location in patent: experimental part Kini, Suvarna G.; Bhat, Anilchandra R.; Bryant, Byron; Williamson, John S.; Dayan, Franck E. [European Journal of Medicinal Chemistry, 2009, vol. 44, # 2, p. 492 - 500]
[4]Miyazaki, Takahiro; Kasai, Shinsei; Ogiwara, Yohei; Sakai, Norio [European Journal of Organic Chemistry, 2016, vol. 2016, # 5, p. 1043 - 1049]
[5]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN107162913, 2017, A Location in patent: Paragraph 0190; 0191

6
[ 39515-51-0 ]
[ 3739-38-6 ]

Yield	Reaction Conditions	Operation in experiment
76%	With dihydrogen peroxide In water; acetonitrile at 45℃; for 1h; chemoselective reaction;
62%	With potassium hydroxide; silver nitrate In ethanol at 20℃;
	With rat hepatic microsomal aldehyde dehydrogenase; NAD In phosphate buffer; N,N-dimethyl-formamide at 37℃;

	With potassium hydroxide; silver nitrate In ethanol
	With potassium permanganate Alkaline aq. solution;
	Multi-step reaction with 2 steps 1: potassium cyanide; potassium iodide / 24 h / 75 - 80 °C 2: sodium hydroxide / water / 20 °C
	With potassium permanganate

Reference： [1]Location in patent: experimental part Lakouraj, Moslem Mansour; Aghajani, Bahareh; Mokhtary, Masoud [Phosphorus, Sulfur and Silicon and the Related Elements, 2010, vol. 185, # 12, p. 2393 - 2401]
[2]Master, Hoshang E.; Khan, Shabana I.; Poojari, Krishna A. [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 16, p. 4891 - 4899]
[3]Martini, Robert; Murray, Michael [Chemical Research in Toxicology, 1996, vol. 9, # 1, p. 268 - 276]
[4]Master, Hoshang E.; Khan, Shabana I.; Poojari, Krishna A. [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 7, p. 1249 - 1251]
[5]Location in patent: experimental part Kini, Suvarna G.; Bhat, Anilchandra R.; Bryant, Byron; Williamson, John S.; Dayan, Franck E. [European Journal of Medicinal Chemistry, 2009, vol. 44, # 2, p. 492 - 500]
[6]Atta, Ananta Kumar; Kim, Seul-Bi; Cho, Dong-Gyu [Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 2070 - 2072]
[7]Popov; Korchagina; Lobasenko; Pavel'Ev [Russian Journal of General Chemistry, 2014, vol. 84, # 11, p. 2264 - 2266][Zh. Obshch. Khim., 2014, vol. 84, # 11, p. 1906 - 1908,3]

7
[ 3739-38-6 ]
[ 101-84-8 ]
[ 39515-51-0 ]

Yield	Reaction Conditions	Operation in experiment
97 % Spectr.	With hydrogen; 2,2-dimethylpropanoic anhydride In tetrahydrofuran at 80℃; for 24h;

Reference： [1]Nagayama; Shimizu; Yamamoto [Bulletin of the Chemical Society of Japan, 2001, vol. 74, # 10, p. 1803 - 1815]

8
C₂₀H₁₈N₂O₃S [ No CAS ]
[ 3739-38-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With silica-supported selenamide; dihydrogen peroxide In tetrahydrofuran at 55℃; for 70h;
90%	With poly(diselanediyl-1,2-phenylene); dihydrogen peroxide In tetrahydrofuran for 24h; Heating;

Reference： [1]Giurg; Brzaszcz; Mlochowski [Polish Journal of Chemistry, 2006, vol. 80, # 3, p. 417 - 428]
[2]Giurg; Said; Syper; Mlochowski [Synthetic Communications, 2001, vol. 31, # 20, p. 3151 - 3159]

9
[ 3739-38-6 ]
[ 497233-85-9 ]
N-(3-{4-[3-(7-chloro-quinolin-4-ylamino)-propyl]-piperazin-1-yl}-propyl)-3-phenoxy-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 4h;

Reference： [1]Ryckebusch, Adina; Deprez-Poulain, Rébecca; Maes, Louis; Debreu-Fontaine, Marie-Ange; Mouray, Elisabeth; Grellier, Philippe; Sergheraert, Christian [Journal of Medicinal Chemistry, 2003, vol. 46, # 4, p. 542 - 557]

10
[ 13826-35-2 ]
[ 3739-38-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With methyl 3,5-bis((1H-1,2,4-triazol-1-yl)methyl)benzoate; oxygen; sodium acetate; nickel dibromide at 120℃; for 96h;
82%	With C₁₄H₁₄N₆O₂; oxygen; sodium acetate; palladium diacetate at 120℃; for 72h;
	With chromium(VI) oxide

Reference： [1]Urgoitia; Sanmartin; Herrero; Domínguez [Chemical Communications, 2015, vol. 51, # 23, p. 4799 - 4802]
[2]Urgoitia, Garazi; Maiztegi, Ainhoa; Sanmartin, Raul; Herrero, María Teresa; Domínguez, Esther [RSC Advances, 2015, vol. 5, # 125, p. 103210 - 103217]
[3]Gobec, Stanislav; Brozic, Petra; Rizner, Tea Lanisnik [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 23, p. 5170 - 5175]

11
1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl-amine dihydrochloride [ No CAS ]
[ 3739-38-6 ]
C₂₉H₂₇FN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With WSC*HCl; benzotriazol-1-ol; triethylamine In dichloromethane at 20℃;

Reference： [1]Sato, Ippei; Morihira, Koichiro; Inami, Hiroshi; Kubota, Hirokazu; Morokata, Tatsuaki; Suzuki, Keiko; Hamada, Noritaka; Iura, Yosuke; Nitta, Aiko; Imaoka, Takayuki; Takahashi, Toshiya; Takeuchi, Makoto; Ohta, Mitsuaki; Tsukamoto, Shin-ichi [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 1, p. 144 - 156]

12
[ 3739-38-6 ]
[ 206761-84-4 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1998,vol. 37,p. 1254 - 1257

13
[ 642085-12-9 ]
[ 3739-38-6 ]
N-[4-fluoro-3-(pyrazin-2-yloxymethyl)-phenyl]-3-phenoxy-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20℃;	3.a A stirred solution of [4-FLUORO-3- (PYRAZIN-2-YLOXYMETHYL)-] phenylamine (0.46 mmol) in dry DMF (4ml) was treated with EDCI (0.55 mmol) and HOBt (0.55 [MMOL).] 3-Phenoxy benzoic acid (0.59 mmol) was added and the reaction mixture stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was washed with saturated bicarbonate solution and brine solution, then the organic layer was separated, dried [(MGSO4),] filtered and evaporated. The residue was purified by column chromatography on silica, eluting with mixtures of petroleum ether and ethyl acetate to afford the desired product. MS (ES): m/e 416 (M+H).

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2004/4720, 2004, A1 Location in patent: Page/Page column 79

14
erythro-4-Methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester [ No CAS ]
[ 3739-38-6 ]
(+/-)-erythro-4-methyl-2-(3-phenoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester [ No CAS ]
(+/-)-threo-4-methyl-2-(3-phenoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane	15.18.2 Step 2) Preparation of (+/-)-threo and (+/-)-erythro-4-Methyl-2-(3-phenoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester To a stirred solution of the product of step I (combined with a second batch of similarly prepared material; 2.30 g, 11.2 mmol) and 3-phenoxybenzoic acid (2.44 g, 11.4 mmol) in methylene chloride was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.19 g, 11.4 mmol) and a catalytic amount of 4-(dimethylamino)pyridine. After overnight stirring, the reaction mixture was washed with aqueous sodium bicarbonate solution, dried (magnesium sulfate) and concentrated. The resulting crude product was purified by flash chromatography over silica (hexanes/ethyl acetate) to afford 1.00 g (24%) of product as a white solid: 1H NNR (CDCl3) δ 7.53-6.86 (m, 13H), 5.16-4.91 (m, 1H), 4.90-4.47 (m, 2H), 3.76-3.15 (m, 4H), 1.48 (d, J=7.0 Hz, 3H) ppm. MS[(ES]) m/z 402 (M+H+).

Reference： [1]Current Patent Assignee: SANOFI - US2005/176761, 2005, A1 Location in patent: Page/Page column 16-17

15
[ 862506-86-3 ]
[ 3739-38-6 ]
(S)-2-(3-phenoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid(6-pentylpyridin-3-yl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform	3.6.3 To a stirred solution of the product of step 2 and 3-phenoxybenzoic acid (0.514 g, 2.40 mmol) in chloroform (10 mL) was added 1-[3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.460 g, 2.40 mmol) and a catalytic amount of 4-(dimethylamino)pyridine. The reaction was allowed to proceed overnight and then worked up as in step 1. The resulting pale green solid was purified by flash chromatography (methylene chloride/methanol) to afford 0.704 g (67% overall) of product as a pale amber, foamy solid. In chloroform-d solvent, the proton NMR spectra of this compound appears as an 8:2 mixture of rotamers: 1H NMR (CDCl3) δ 9.26 (s, 1H), 8.51 (s, 0.8H), 8.41-8.25 (m, 0.2H), 7.93 (d, J=7.3 Hz, 0.8H), 7.77-7.65 (m, 0.2H), 7.48-6.83 (m, 14H), 5.19 (t, J=6.7 Hz, 0.8H), 5.19-5.02 (m, 0.2H), 4.83-4.74 (m, 0.2H), 4.62 (d, J=15.2 Hz, 0.8H), 4.53-4.38 (m, 1H), 3.55-3.39 (m, 1H), 3.21-2.97 (m, 1B), 2.80-2.65 (m, 2H), 1.74-1.59 (m, 2H), 1.40-1.23 (m, 4H), 0.88 (t, J=6.5 Hz, 3H) ppm

Reference： [1]Current Patent Assignee: SANOFI - US2005/176761, 2005, A1 Location in patent: Page/Page column 12

16
ethyl 1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate [ No CAS ]
[ 3739-38-6 ]
[ 862506-69-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform	2.1 EXAMPLE 2; (+/-)-2-(3-Phenoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Intermediate 2); Step 1) Preparation of (+/-)-2-(3-Phenoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester To a stirred solution of (+-)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester (6.26 g, 30.5 mmol) and 3-phenoxybenzoic acid (7.19 g, 33.6 mmol) in chloroform (150 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.43 g, 33.5 mmol). The reaction was allowed to proceed overnight and then washed with aqueous sodium bicarbonate solution, dried (sodium sulfate) and concentrated. The crude product was purified by flash chromatography over silica (hexanes/ethyl acetate) to afford 12.07 g (99%) of product as a colorless gum. In chloroform-d solvent, the proton NMR spectra of this compound appears as a 55:45 mixture of rotamers: 1H NMR (CDCl3) δ 7.46-6.90 (m, 13H), 5.46 (t, J=5.6 Hz, 0.55H), 5.18 (d, J=17.6 Hz, 0.45H), 4.80-4.73 (m, 0.45H), 4.68-4.50 (m, 1.55H), 4.22-4.07 (m, 1.10H), 4.05-3.92 (m, 0.90H), 3.34-3.19 (m, 1.55H), 3.16-3.06 (m, 0.45H), 1.19 (t, J=7.1 Hz, 1.65H), 1.04 (t, J=7.1 Hz, 1.35H) ppm.

Reference： [1]Current Patent Assignee: SANOFI - US2005/176761, 2005, A1 Location in patent: Page/Page column 11

17
(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol [ No CAS ]
[ 3739-38-6 ]
N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃;	107 To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.28 mmol) in acetonitrile (20 ml) were added 3-phenoxybenzoic acid (274 mg, 1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (368 mg, 1.92 mmol) and 1-hydroxy-1H-benzotriazole (196 mg, 1.28 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (400 mg, 61%). mp 144-145°C IR ν maxKBr cm-1: 1644, 1580, 1510, 1491, 1481. Anal. Calcd for C29H23F4NO3·0.1H2O: C, 68.13; H, 4.57; N, 2.74 Found: C, 67.85; H, 4.51; N, 2.53.1H-NMR (CDCl3)δ: 2.! 80-3.00 (2H, m), 3.30-3.70 (1H, m), 4.50-4.64 (1H, m), 5.05 (1H, d, J = 3.2 Hz) , 6.11 (1H, d, J = 8.6 Hz) , 6.96-7.52 (17H, m).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1362846, 2003, A1 Location in patent: Page/Page column 84

18
[ 617244-65-2 ]
[ 3739-38-6 ]
N-(2-dimethylamino-ethyl)-2,6-dimethoxy-3-(3-phenoxy-benzoylamino)-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-amino-N-(2-dimethylamino-ethyl)-2,6-dimethoxy-benzamide; 3-phenoxybenzoic acid With dmap; PS-DCC; benzotriazol-1-ol In dichloromethane for 72h; Stage #2: With PS-Trisamine In dichloromethane for 1h; Stage #3: With PS-isocyanate In dichloromethane for 1h;	37 Example 37 N- (2-Dimethylamino-ethyl)-2, 6-dimethoxy-3- (3-phenoxy-benzoylamino)-benzamide A flask was charged with N-(N, N-dimethylaminoethylamine)-3-amino-2, 6- dimethoxybenzamide (80 mg, 0.32 mmol), hydroxybenzotriazole (43 mg, 0.32 mmol), N, aminopyridine (1 crystal) and 3-phenoxybenzoic acid (79 mg, 0.40 mmol). Dichloromethane (8 pL) was added and the solution was stirred under air before PS-DCC (350 mg, approx. 0.64 mmol) was added. Stirring continued for 72 h. Then PS-trisamine (100 mg) was added and stirred for 1 h before PS-iscocyanate (100 mg) was added and the resulting suspension stirred for a futher 1 h. The resins were removed by filtration and further washed with dichloromethane (50 gel) and the combined organics were reduced in vacuo to give crude material which was chromatographed (Al203, dichloromethane/methanol/triethylamine, 90: 9: 1) to give the title compound. 1H NMR (300 MHz, CDCI3) : 8 8.42-8-38 (1 H, d), 8.35-8. 28 (1 H, br s, NH), 7.48-7. 35 (5H, m), 7.25-7. 10 (2H, m), 7.08-7. 10 (2H, d), 6.75-7. 69 (1H, d), 6.68-6. 48 (1H, brs, NH), 3.89 (3H, s, MeO), 3.83 (3H, s, MeO), 3.58-3. 52 (2H, m), 2.53-2. 49 (2H, m), 2.25 (6H, s, Me2N).

Reference： [1]Current Patent Assignee: 7TM PHARMA AS - WO2003/87045, 2003, A1 Location in patent: Page/Page column 59

19
[ 892841-20-2 ]
[ 3739-38-6 ]
N-{2-[methyl-(1-methyl-pyrrolidin-3-ylmethyl)-amino]-benzooxazol-5-yl}-3-phenoxy-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With HATU In dichloromethane at 20℃;	37 Combine rac-N2-methyl-N2-( 1 -methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.034 g, 0.131 mmol), 3-phenoxy-benzoic acid (0.042 g, 0.196 mmol), HATU (0.050 g, 0.131 mmol), polystyrene-bound diisopropylamine (0.327 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (10 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2ZMeOH. Concentrate the solution to yield a yellow residue. EPO Dilute with CH2Cl2 and wash with 1.0M NaOH (2 x 25mL), dry over Na2SO4, filter, and concentrate in vacuo after adsorption onto silica gel. Subject the mixture to flash column chromatography on an ISCO Companion (4 g column, 10% 2M NH3 in MeOH/CH2Cl2) to yield the desired compound as a white oil. Dilute with CH2Cl2 and n-hexane and concentrate in vacuo. Pump for 2 h to yield the desired compound as a white solid (0.027 g, 45%). mass spectrum (m/e): 457.3 (M+l), 455.3 (M-I). 1H NMR (400 MHz, CDCl3): δ 7.84 (s, IH), 7.56 (d, J = 7.6 Hz, IH), 7.51-7.45 (m, 2H), 7.41 (t, 7= 8.0 Hz, IH), 7.37-7.29 (m, 3H), 7.20-7.10 (m, 3H), 7.04- 7.00 (m, 2H), 3.59-3.48 (m, 2H), 3.18 (s, 3H), 2.74-2.50 (m, 4H), 2.38-2.33 (m, IH), 2.35 (s, 3H), 2.05-1.95 (m, IH), 1.59-1.49 (m, IH).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2006/66173, 2006, A2 Location in patent: Page/Page column 56-57

20
[ 902765-75-7 ]
[ 3739-38-6 ]
2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(3-phenoxybenzoyl)piperazin-1-yl]thieno[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 20℃;	136 EXAMPLE 1362-[(4S)-2,2-Dimethyl-1 , 3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(3-phenoxybenzoyl)piperazin-1- yl]thieno[2,3-d]pyrimidine; To a mixture of the pyrimidine of Example 25 (0.106 g) in THF (5 mL) was added diisopropylethylamine (0.11 mL), HATU (0.106 g) and 3-phenoxybenzoic acid (0.06 g). The mixture was stirred overnight at room temperature. THF was then removed under reduced pressure and the resulting crude mixture was purified on silica gel using ethyl acetate and hexanes (70/30) to give 0.13 g of the title compound. MS (ESI+) m/z 575.41 (M+H)+. 1H NMR (400 MHz, CDCI3). δ 7.40-7.36 (m, 3H), 7.25 (m, 2H), 7.15 (m, 4H), 6.84 (s, 1 H), 4.51 (m, 2H), 4.31 (m, 1 H), 4.15 (m, 1H), 3.9-3.5 (br m, 9H), 2.85 (q, 2H), 1.59 (s, 3H), 1.37 (s, 3H), 1.32 (t, 3H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2006/79916, 2006, A1 Location in patent: Page/Page column 146

21
[ 79-37-8 ]
[ 3739-38-6 ]
[ 3586-15-0 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane	4 3-(2-Pyridyl)-5-(3-phenoxyphenyl)-1,2,4-oxadiazole 3-Phenoxybenzoic acid (214 mg, 1.0 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 3-phenoxybenzoyl chloride.
	In dichloromethane; N,N-dimethyl-formamide	23 EXAMPLE 23 The 3-phenoxybenzoyl chloride used as a starting material was prepared as follows: Oxalyl chloride (0.11 ml) was added dropwise to a stirred mixture of 3-phenoxybenzoic acid (0.214 g), DMF (a few drops) and methylene chloride (4 ml) which had been cooled to 0° C. The mixture was stirred at ambient temperature 24 hours. The solvent was evaporated to give the required acid chloride which was used without further purification.
1.12 g (53%)	In diethyl ether; dichloromethane	6.a (a) (a) 3-Phenoxybenzoyl Chloride: This compound was prepared as generally described in (Patent Publication No. GB 1052390). To 3-phenoxybenzoic acid (1.95 g, 9.10 mmol) dissolved in CH2Cl2 (45 mL) was added oxalyl chloride (0.89 mL, 10.01 mmol) followed by a drop of DMF. The reaction mixture was stirred overnight at rt and the solvent was removed in vacuo. The residue was taken up in Et2O, and the liquid was carefully decanted away from any remaining solid. The Et2O was evaporated and the resulting crude product was purified by short path vacuum distillation (bp=139° C./3 mm Hg) to give 1.12 g (53%) of a clear liquid: IR (neat) 1755, 1584 cm-1; 1H NMR (CDCl3) δ 7.02-7.05 (m, 2H), 7.16-7.21 (m, 1H), 7.29-7.33 (m, 1H), 7.37-7.49 (m, 3H), 7.70-7.71 (m, 1H), 7.84-7.87 (m, 1H).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US2003/55085, 2003, A1
[2]Current Patent Assignee: ASTRAZENECA PLC - US6579872, 2003, B1
[3]Current Patent Assignee: PFIZER INC - US6548494, 2003, B1

22
[ 3739-38-6 ]
[ 497-19-8 ]
[ 79-22-1 ]
(-)-2-[5-[2,5-Dioxo-1-(3-phenoxybenzyl)imidazolidin-4-yl]methyl}-1H-indol-3-yl]ethylamine maleate hydrate [ No CAS ]
[ 73258-84-1 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; triethylamine In tetrahydrofuran; ethyl acetate	S.11.a (a) (a) 3-Phenoxybenzamide Triethylamine (5.6 g) was added at 0° C. under N2 to a stirred solution of 3-phenoxybenzoic acid (10.7 g, Aldrich) in THF (75 ml), followed by the addition of methyl chloroformate (4.7 g) at less than 5° C. After additions were complete, the mixture was stirred at 0° C. for 30 minutes. 0.88 Ammonia (30 ml) was added and the mixture stirred at room temperature for 20 hours, then evaporated in vacuo and the residue taken up in ethyl acetate (100 ml) and water (100 ml). The aqueous phase was separated, extracted with ethyl acetate and the combined ethyl acetate solutions washed with 5% w/v aqu. Na2 CO3 (2*50 ml), 2N aqu. HCl (50 ml) and water (100 ml), dried over Na2 SO4 and evaporated in vacuo to give the desired product as a colourless solid which was recrystallized from ethyl acetate/60-80 pet. ether (1:2 v/v), mp 125°-127° C. (6.5 g). The 200 MHz 1 H NMR was consistent with the proposed structure.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US5225431, 1993, A

23
[ 197445-18-4 ]
[ 3739-38-6 ]
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-3-phenoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In thionyl chloride; dichloromethane; toluene	87 (R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-3-phenoxybenzamide Example 87 (R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-3-phenoxybenzamide 3-Phenoxybenzoic acid (1.0 g, 4.7 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (99 mg, 0.42 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (99 mg, 0.41 mmol) and triethylamine (83 μL, 0.42 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2 SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 120 mg (68%) of the title compound as an oil.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US6124283, 2000, A

24
[ 197446-21-2 ]
[ 3739-38-6 ]
(R)-N-[5-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-3-phenoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In thionyl chloride; dichloromethane; toluene	120 (R)-N-[5-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-3-phenoxybenzamide Example 120 (R)-N-[5-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-3-phenoxybenzamide 3-Phenoxybenzoic acid (1.0 g, 4.7 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 30 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (70 mg, 0.30 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-5-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (70 mg, 0.28 mmol) and triethylamine (55 μL, 0.42 mmol) in methylene chloride (25 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2 SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 45 mg (36%) of the title compound as a solid foam: [α]21D +24° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 441 (18, M+).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US6124283, 2000, A

25
[ 3739-38-6 ]
[ 73258-84-1 ]
[ 1694-29-7 ]
[ 144526-76-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	In hexane; ethyl acetate	6.A 6A. 6A. 5-Acetyl-4-methyl-2-(3-phenoxyphenyl)oxazole A mixture of 3-phenoxybenzamide (2.13 g, 10 mmol), 3-phenoxybenzoic acid (4.28 g, 20 mmol), and 3-chloropenta-2,4-dione (0.44 g, 3.3 mmol) was heated to 180° C. under stirring for 23 h. The hot mixture was poured into 1N aqueous sodium hydroxide (100 ml), and extracted with diethyl ether (100+2*50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), dried over magnesium sulfate, and evaporated to dryness. Purification by silica gel column chromatography (135 g, 16.7% ethyl acetate in n-hexane) afforded the titled compound as solids in 94% yield: 1H NMR (CDCl3) δ7.88-7.83 (1H, m), 7.77-7.53 (1H, m), 7.49-7.34 (3H, m), 7.18-7.12 (2H, m), 7.07-7.00 (2H, m), 2.55 (3H, s), 2.54 (3 H, s).

Reference： [1]Current Patent Assignee: PFIZER INC - US5464849, 1995, A

26
[ 3739-38-6 ]
[ 109-63-7 ]
[ 13826-35-2 ]

Yield	Reaction Conditions	Operation in experiment
83%	With mercury In tetrahydrofuran; diethyl ether; water	1 EXAMPLE 1 EXAMPLE 1 A 22-liter, 4-necked glass reaction vessel equipped with a mechanical stirrer, thermometer, pressure-equalizing addition funnel and reflux condenser vented to a mercury bubbler was charged with 567 grams (14.25 moles plus 5% excess) of sodium borohydride, and flushed for 0.5 hour with dry nitrogen. Tetrahydrofuran (7.5 liters) was then added and the resulting slurry was cooled to 5°C with stirring using an external dry ice/isopropyl alcohol bath. The addition funnel was charged with 2.33 liters (19 moles) of boron trifluoride diethyl etherate which was then added dropwise to the reaction mixture with stirring over a 2 hour period while maintaining a reaction temperature of 0°-5°C. After stirring the reaction mixture for an additional 0.5 hour at 0°-5°C, a solution of 3860 grams (18 moles) of m-phenoxybenzoic acid in tetrahydrofuran was added dropwise over a 4 hour period while maintaining a reaction temperature of 0°-10°C. When the addition was complete, the reaction mixture was stirred for 12 hours at 20°C followed by 2 hours at 40°C. The reaction mixture was then transferred to a 10 gallon bottle containing 6 liters of water and 8 liters of diethyl ether. After mixing thoroughly, the aqueous layer was removed and the organic layer was extracted with water (1 * 4 liters), extracted with aqueous saturated sodium bicarbonate solution (1 * 4 liters), extracted with aqueous saturated sodium chloride solution (1 * 4 liters), dried over anhydrous potassium carbonate, filtered, and concentrated on a rotary evaporator. Short-path distillation gave 3000 grams (83% yield) of m-phenoxybenzyl alcohol, bp 135°-140°C/0.10 mm, n20 D 1.5935.
	With mercury In tetrahydrofuran	2 EXAMPLE 2 EXAMPLE 2 A 500-milliliter, 4-necked glass reaction vessel equipped with a magnetic stirring bar, pressure-equalizing addition funnel, thermometer, and reflux condenser vented to a mercury bubbler was charged with 9.6 grams (0.248 mole plus 5% excess) of sodium borohydride and 64 grams (0.30 mole) of m-phenoxybenzoic acid and flushed 10 minutes with dry nitrogen. The reaction vessel was cooled in an external ice/water bath as 0.2 liter of tetrahydrofuran was added dropwise followed by 40.6 milliliters (0.33 mole) of boron trifluoride diethyl etherate over a 1 hour period while maintaining a temperature of 0°-10°C. The reaction mixture was then stirred for 12 hours at 20°C followed by 2 hours at 40°C. The product was isolated using a procedure similar to that described in Example 1 giving 48 grams (80% yield) of m-phenoxybenzyl alcohol, n20 D 1.5935.

Reference： [1]Current Patent Assignee: ALDRICH BORANES - US3978140, 1976, A
[2]Current Patent Assignee: ALDRICH BORANES - US3978140, 1976, A

27
[ 666859-55-8 ]
[ 3739-38-6 ]
[ 666859-02-5 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: 3-phenoxybenzoic acid With oxalyl dichloride In DMF (N,N-dimethyl-formamide); dichloromethane at 20℃; for 1h; Stage #2: 3-(2-amino-5-bromophenyl)-4,5-dihydro-1,2,4-oxadiazol-5-one In pyridine; dichoromethane at 20℃;	16 N-[4-bromo-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl-3-phenoxybenzamide, PHA-666967 3-Phenoxybenzoic acid (, [236] mg, 1.1 mmol, Aldrich) was dissolved in dry [CH2C12] (10 mL) under N2 and treated with DMF (20 [PL)] followed by oxalyl chloride (0.192 mL, 2.2 mmol). Gas evolved as the mixture was stirred for one hour at RT. The solvent and excess oxalyl chloride were evaporated and the resultant residue was taken up in [CH2CL2] (10 mL). [3- (2-amino-5-bromophenyl)-1,] 2,4-oxadiazol-5 (4H) -one (256 mg, 1.0 mmol) was added as a solution in dry pyridine (4 mL) and the yellow solution was stirred at RT overnight. The reaction was diluted to 75 mL with [CH2C12,] and the organic layer was washed 2x with [1.] OM [HC1] causing the product to precipitate. The organic layer containing the precipitated product was evaporated, and the residue was re-crystallized from hot EtOH/THF. The resultant product was dried at [100 C] under vacuum to afford 234 mg (47%) of pale yellow [NEEDLES. 1H] NMR (400 MHz, DMSO-d6) [8 12.] 92 (s, [1] H), 10.46 (s, [1] H), 8.04 (d, J= 8.9 Hz, 1 H), 7.91 (d, [J=] 2.3 Hz, [1] H), 7.84 (dd, [J=] 8.7, 2.3 Hz, 1 H), 7.70 (d, [J=] 7.7 Hz, 1 H), 7. [59] (t, J= 8.0 Hz, 1 H), 7.55 (t, J= 2.1 Hz, 1 H), 7.41-7. 47 (m, 2 H), 7.27 (dd, J= 7.7, 2.1 Hz, 1 H), 7.20 (t, J= 7.4 Hz, 1 H), 7.07-7. 12 [(M,] 2 H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/18461, 2004, A2 Location in patent: Page 31

28
[ 3739-38-6 ]
[ 585-32-0 ]
[ 913389-91-0 ]

Yield	Reaction Conditions	Operation in experiment
97%		3-Phenoxybenzoic acid (3.00 g, 14.0 mmol) was dissolved in DMF (45 mL), and the solution was added with EDCI (4.03 g, 21.0 mmol) and HOBT monohydrate (1.07 g, 7.00 mmol) under ice-cooling, followed by stirring at the same temperature for 5 minutes. Then, the mixture was added with cumylamine (4.03 mL, 28.0 mmol) and stirred at room temperature for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by slurry using hexane to obtain 3-phenoxy-N-(1-methyl-1-phenylethyl)benzamide (4.51 g, yield 97percent). APCI-MSm/z: 332 [M+H]+; 1H-NMR (CDCl3)delta(ppm): 1.81 (m, 6H), 6.36 (s, 1H), 7.01 (m, 2H), 7.12 (m, 2H), 7.21-7.46 (m, 10H).

Reference： [1]Patent: EP2108642,2009,A1 .Location in patent: Page/Page column 104

29
[ 3691-34-7 ]
[ 3739-38-6 ]
[ 617244-38-9 ]

Yield	Reaction Conditions	Operation in experiment
3%	Stage #1: 3-phenoxybenzoic acid With PS-DCC; benzotriazol-1-ol In dichloromethane for 0.166667h; Stage #2: N-(N,N-dimethylaminopropyl)-4-amino-2-methoxybenzamide In dichloromethane for 72h; Stage #3: With PS-Trisamine In dichloromethane for 2h;	7 Example 6 N- (3-Dimethylamino-propyl)-2-methoxy-4- (4-phenoxy-benzoylamino)-benzamide N- (N, N-dimethylaminopropyl)-4-amino-2-methoxybenzamide was prepared according to the experiment described in Ex 3. In a flask were placed PS-DCC (1.2 g, 1.35 mmol/g), dichloromethane (15 VtL), 4-phenoxy benzoic acid (0.26 g, 1.2 mmol) and HOBt (0.18 g, 1.35 mmol) and the mixture was gently stirred for 10 minutes before N- (N, N- dimethylaminopropyl)-4-amino-2-methoxybenzamide (0.20g, 0.80 mmol) was added. The reaction was stirred for three days when PS-trisamine (1.0 g, 3.38 mmol/g) was added. After 2h the resins were filtered off and rinsed with dichloromethane (20 IlL). The solvent was removed under vacuum giving the crude product. Chromatography (Silica, dichloromethane/methanol/ammonia, 200: 10: 1) yielded 8 mg (2%) of the title product NMR (300 MHz, CDCl3) : 8 1.8 (dt, 2H), 2.28 (s, 3H), 2.42 (t, 2H), 3.53 (q, 2H), 4.02 (s, 3H), 6.91 (d, 1H) and 7.89 (d, 2H).

Reference： [1]Current Patent Assignee: 7TM PHARMA AS - WO2003/87045, 2003, A1 Location in patent: Page/Page column 49

30
C₂₇H₄₂N₄O₆ [ No CAS ]
[ 3739-38-6 ]
C₄₀H₅₀N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃;	To a stirred solution of compound 15 (0.06 mmol) and 3-phenoxybenzoic acid (51 mg, 0.24 mmol) in 1.5 ml DMF was added TBTU (77 mg, 0.24 mmol) at room temperature. The mixture was stirred at room temperature overnight. After the completion of the reaction (LC-MS), DMF was removed using high vacuum. The residue was dissolved in 3 ml DCM and then purified by preparative TLC (1:3 hexanes/ethyl acetate) to give compound 20 (36 mg, 83%) as a white semi-solid. MS: 713.0 (M-H).

Reference： [1]Current Patent Assignee: SEQUOIA PHARMACEUTICALS, INC. - WO2010/21717, 2010, A2 Location in patent: Page/Page column 45-46

31
[ 870221-77-5 ]
[ 3739-38-6 ]
[ 870231-44-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine; HATU In chloroform at 20℃; for 5h;

Reference： [1]Location in patent: experimental part Cee, Victor J.; Schenkel, Laurie B.; Hodous, Brian L.; Deak, Holly L.; Nguyen, Hanh N.; Olivieri, Philip R.; Romero, Karina; Bak, Annette; Be, Xuhai; Bellon, Steve; Bush, Tammy L.; Cheng, Alan C.; Chung, Grace; Coats, Steve; Eden, Patrick M.; Hanestad, Kelly; Gallant, Paul L.; Gu, Yan; Huang, Xin; Kendall, Richard L.; Lin, Min-Hwa Jasmine; Morrison, Michael J.; Patel, Vinod F.; Radinsky, Robert; Rose, Paul E.; Ross, Sandra; Sun, Ji-Rong; Tang, Jin; Zhao, Huilin; Payton, Marc; Geuns-Meyer, Stephanie D. [Journal of Medicinal Chemistry, 2010, vol. 53, # 17, p. 6368 - 6377]

32
[ 3739-38-6 ]
[ 2592-95-2 ]
[ 1260112-69-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide for 0.25h;	ΛL((35',3αi?,6)S',6αi?)-6-Aminohexahydrofuro[3,2-6]furan-3-yl)-3-phenoxybenzamide (C12)A mixture of 3-phenoxybenzoic acid (12.0 g, 56.0 mmol), 1 -hydroxybenzotriazole (7.6 g, 56.3 mmol) and l-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (13.0 g, 68.1 mmol) in dry DMSO (50 ml) was stirred for 15 min. Water (300 ml) was added, and the solution was extracted with ethyl acetate (350 ml X 2), washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure below 30 0C until ca 80 ml were left.
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.5h;	6.1.2. Synthesis of the amide-modified farnesylcysteine methylester intermediate General procedure: The appropriate carboxylic acid (1.0 equiv) was charged to a dry round bottom flask and was dissolved in dimethylformamide (DMF). Diisopropylethylamine (1.1 equiv), HOBT (1.1 equiv) and HBTU (1.1 equiv) were added to this and the contents were allowed to react at 0 °C for 30 min. This was followed by addition of a solution of farnesylcysteine methylester in DMF. The contents were allowed to react for 2 h. The reaction was monitored by TLC analysis. On completion of the reaction, 10% aqueous citric acid was added to the reaction mixture and the product was extracted using ethylacetate (20 mL) as the solvent. The solvent was removed under vacuum utilizing a rotary evaporator and the residue was loaded on a short (2-3 inches) silica gel plug. The silica gel plug was flushed with 3% methanol in dichloromethane to obtain the crude coupling product.

Reference： [1]Current Patent Assignee: Firmenich International SA - WO2011/2871, 2011, A2 Location in patent: Page/Page column 43
[2]Location in patent: experimental part Majmudar, Jaimeen D.; Hodges-Loaiza, Heather B.; Hahne, Kalub; Donelson, James L.; Song, Jiao; Shrestha, Liza; Harrison, Marietta L.; Hrycyna, Christine A.; Gibbs, Richard A. [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 283 - 295]

33
[ 3739-38-6 ]
[ 73789-56-7 ]
[ 82-86-0 ]
[ 1309930-26-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	In acetonitrile at 20℃; for 0.25h; Sonication;	1 2.3 Ultrasound-promoted typical procedure for synthesis of title compounds General procedure: The carboxylic acid derivatives (1.0mmol), acenaphthoquinone (182mg, 1.0mmol), (N isocyanimino)triphenylphosphorane (302mg, 1.0mmol) and CH3CN (10mL) were added into a 25mL round bottomed flask. During the ultrasound irradiation, the temperature of the mixture was controlled with ice bath (temperature was maintained in room temperature). The reaction mixture was sonicated under 100W for the period of time (The reaction was monitored by TLC). The solvent was removed under reduced pressure, and the viscous residue was purified by PLC [silica gel (F254) powder; petroleum ether/ethyl acetate 4:1]. The authenticity of the samples (4a-4p) was established by their 1H NMR, 13C NMR and MS.
75%	In water at 20 - 26℃; for 15h; Green chemistry;	synthesis of sterically congested2,5-disubstituted 1,3,4-oxadiazoles derivatives (4a-p) General procedure: A mixture of N-isocyanimino-triphenylphosphorane (Ph3PNNC) (1.0 mmol, 0.302 g), acenaphthoquinone (1.0 mmol,0.182 g), and an aromatic carboxylic acid (1.0mmol (1a: 0.136 g,1b: 0.201 g, 1c: 0.147 g, 1d: 0.136 g, 1e: 0.178 g, 1f: 0.173 g,1g: 0.214 g, 1h: 0.215 g, 1i: 0.172 g, 1j: 0.157 g, 1k: 0.140 g, 1l:0.136 g, 1m: 0.152 g, 1n: 0.182 g, 1o: 0.136 g, 1p: 0.150 g.)) indistilledwater (5 mL) was stirred at RT (20-26°C) for 15 h. Aftercompleting the reaction, the resulting mixture was extractedin dichloromethane. The solvent was removed under reducedpressure, and the viscous residue was purified by PLC (silica gelpowder, F254; petroleum ether:ethyl acetate (4:1)).
72%	In acetonitrile at 20℃; for 24h;

Reference： [1]Rouhani, Morteza; Ramazani, Ali; Joo, Sang Woo [Ultrasonics Sonochemistry, 2015, vol. 22, p. 391 - 396]
[2]Jafari, Ali; Ramazani, Ali; Sadri, Fariba; Joo, Sang Woo [Phosphorus, Sulfur and Silicon and the Related Elements, 2016, vol. 191, # 2, p. 316 - 321]
[3]Location in patent: experimental part Ramazani, Ali; Zeinali Nasrabadi, Fatemeh; Mashhadi Malekzadeh, Asemeh; Ahmadi, Yavar [Monatshefte fur Chemie, 2011, vol. 142, # 6, p. 625 - 630]

34
[ 60677-14-7 ]
[ 3739-38-6 ]

Yield	Reaction Conditions	Operation in experiment
100%		INTERMEDIATE 73 - PREPARATION of 3-Phenoxybenzoic acid. Ethyl 3-phenoxybenzoate (0.220 g; 0.725 mmol) was added to a mixture of NaOH in water (1.5 mL; 2M) and dioxane (1.5 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated in vacuo and extracted with dichloromethane. The aqueous layer was acidified with a 6N solution of hydrochloric acid in water. The precipited product was collected by filtration to yield 0.200 g (quantitative) of the title compound as a white solid which was used without further purifications.ESI/APCI(+): 213 (M-H).
	With water; sodium hydroxide; In ethanol; for 3.0h;Reflux;	General procedure: A mixture of 3a-g (1.85 mmol), sodium hydroxide (80 mg, 2.0 mmol) in ethanol (4 mL) and water (4 mL) was stirred under reflux for 3 h. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (3×10 mL) and water (20 mL). The aqueous layer was separated and made acidic with 2M HCl, then extracted with dichloromethane (3×10 mL). The organic layer was were washed with brine (20 mL), dried over Na2SO4, and then evaporated under reduced pressure to give 4a-g (yields 89.1%-98.8%) as a white solid which could be used directly for the next step without further purication.
0.2 g	With water; sodium hydroxide; In 1,4-dioxane; at 20℃;	Ethyl 3-phenoxybenzoate (0.220 g; 0.725 mmol) was added to a mixture of NaOH in water (1.5 mL; 2M) and dioxane (1.5 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated in vacuo and extracted with dichloromethane. The aqueous layer was acidified with a 6N solution of hydrochloric acid in water. The precipitated product was collected by filtration to yield 0.200 g (quantitative) of the title compound as a white solid which was used without further purifications. [0688] ESI/APCI(+): 213 (M-H).

Reference： [1]Patent: WO2012/80221,2012,A1 .Location in patent: Page/Page column 94
[2]Bulletin of the Korean Chemical Society,2011,vol. 32,p. 2070 - 2072
[3]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 954 - 957
[4]Patent: US2013/274260,2013,A1 .Location in patent: Paragraph 0687-0688

35
[ 3739-38-6 ]
[ 1357390-52-3 ]
[ 1357390-59-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 3-phenoxybenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.333333h; Stage #2: 1-{2-[5-(3-phenoxybenzyl)-1,1-dioxido-1,2,5-thiadiazolidin-2-yl]ethyl}piperazine In N,N-dimethyl-formamide	5.2.14. 1-(3-Phenoxybenzoyl)-4-{2-[5-(3-phenoxybenzyl)-1,1-dioxido-1,2,5-thiadiazolidin-2-yl]ethyl}piperazine (8c) General procedure: To a solution of 4-chlorobenzoic acid (0.62 g; 4 mmol) in dry DMF (20 mL) was added EDCI (1.14 g; 6 mmol) and N-hydroxybenzotriazole monohydrate (0.91 g; 6 mmol) and the mixture was stirred for 20 min. Compound 7b (1.66 g; 4 mmol) was added and stirring was continued overnight. The DMF was removed in vacuo and the residue was taken up in ethyl acetate (120 mL) and washed with water (30 mL) and brine (25 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated, leaving a crude product which was purified by flash chromatography (silica gel/ethyl acetate/hexanes) to give compound 8a as a white solid (0.94 g; 42% yield),

Reference： [1]Location in patent: experimental part Dou, Dengfeng; Mandadapu, Sivakoteswara R.; Alliston, Kevin R.; Kim, Yunjeong; Chang, Kyeong-Ok; Groutas, William C. [European Journal of Medicinal Chemistry, 2012, vol. 47, # 1, p. 59 - 64]

36
[ 3739-38-6 ]
[ 114010-96-7 ]
[ 1356700-00-9 ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: 3-phenoxybenzoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.333333h; Stage #2: 1-(3-phenoxybenzyl)piperazine In N,N-dimethyl-formamide at 20℃;	Representative synthesis of compounds 9a-h General procedure: To a solution of 4-phenoxybenzoic acid (0.32 g; 1.5 mmol) in dry DMF (10 mL) was added EDCI (0.35 g; 1.8 mmol) and the mixture was stirred for 20 min. Compound 8 (0.40 g; 1.5 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in dichloromethane (50 mL), washed with 5% HCl (2 x 20 mL), 5% NaHCO3 (2 x 20 mL), and brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed to give a crude product which was purified by flash chromatography (silica gel/ethyl acetate/hexanes) to give 9a as a colorless oil (0.29 g; 41% yield).

Reference： [1]Dou, Dengfeng; He, Guijia; Mandadapu, Sivakoteswara Rao; Aravapalli, Sridhar; Kim, Yunjeong; Chang, Kyeong-Ok; Groutas, William C. [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 377 - 379]

37
1-benzyl piperazine dihydrobromide [ No CAS ]
[ 3739-38-6 ]
[ 1002995-97-2 ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: 3-phenoxybenzoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 1-benzyl piperazine dihydrobromide With triethylamine In N,N-dimethyl-formamide at 20℃;	General coupling procedure for compounds 1a-i: General procedure: To a solution of appropriate carboxylic acid (2 mmol) in 5 mL dry DMF was added EDCI (0.46 g; 2.4 mmol), and the reaction mixture was stirred at room temperature for 15 min. 1-Benzyl piperazine dihydrobromide (0.68 g; 2 mmol) and TEA (1.0 mL, 7.2 mmol) were added to above solution and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was taken up with ethyl acetate (30 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated to dryness. The crude product was purified by flash chromatography (silica gel/ethyl acetate/hexanes) to give pure products 1a-i.

Reference： [1]Dou, Dengfeng; He, Guijia; Mandadapu, Sivakoteswara Rao; Aravapalli, Sridhar; Kim, Yunjeong; Chang, Kyeong-Ok; Groutas, William C. [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 377 - 379]

38
[ 3739-38-6 ]
[ 1275993-34-4 ]
[ 1360801-97-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 17h;	73.D Step D: ethyl 4-(5-(3-phenoxybenzamido)-2 3'-bipyridin-6'-yloxy cyciohexanecarboxylate To a solution of ethyl 4-(5-amino-2;3'-bipyridin-6'-yloxy)cyclohexanecarboxylate (100 mg, 0.293 mmol) and 3-phenoxy benzoic acid (69 mg, 0.322 rnmol) in CH2CI2 (10 mL) was added HATU (167 mg, 0.440 mmol) and Hunig's base (153 pL, 0.879 mmol). The reaction mixture was stirred at RT for 17 h. The solution was then concentrated and purified by silica gel column chromatography with an ISCO system to yield ethyl 4-(5-(3-phenoxybenzamido)-2,3'- bipyridin-6'-yloxy)cyclohexanecarboxylate as a white solid. LC/MS = 538 [M+l],

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2012/24179, 2012, A1 Location in patent: Page/Page column 69-70

39
[ 3739-38-6 ]
[ 1360802-76-1 ]
[ 1360801-92-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichlromorodifluoromethane at 20℃; for 14h;	68 EXAMPLE 68methyl 3 -(( 2-oxo-4-(5-(3 -phenoxyben2amido)pyridin-2-yl)piperazin- 1 ~yl)methyl benzoateTo a solution of 3-phenoxybenzoic acid (50 mg, 0.23 mmol) in CH2C12 (4 mL) was added 3-((4-(5~aminopyridin-2-yl)~2-oxopiperazin-l-yl)methyl)benzoate (61 mg, 0.179 mmol), HOBT (32 mg, 0.237 mmol), EDCI (50 mg, 0.26 mmol), and ethyldiisopropylamine (0.07 mL, 0.40 mmol). The reaction mixture was stirred at RT for 14 h. CH2CI2 was added, and the organic solution was washed with 1 N NaOH. The combined organic extract was dried (MgS04), filtered, and concentrated. Purification by silica gel chromatography with an ISCO system (eluant: EtOAc/hexane) to yield the title compound as an off white solid. LC/MS = 537 [M+l].

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2012/24179, 2012, A1 Location in patent: Page/Page column 67

40
[ 3739-38-6 ]
[ 942-26-7 ]
[ 1382992-69-9 ]

Yield	Reaction Conditions	Operation in experiment
19%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	EXAMPLE 107 - PREPARATION of N-(2-(5-Chloro-1 H-indol-3-yl)ethyl)-3- phenoxybenzamide. A mixture of 3-phenoxybenzoic acid (0.200 g, 0.934 mmol), 2-(5-chloro-1 H-indol-3- yl)ethanamine hydrochloride (0.215 g; 0.934 mmol), HATU (0.389 g; 1.03 mmol) and N,N- diisopropylethyldiamine (0.402 mL; 2.33 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified twice by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.068 g (19%) of the title compound as a colourless solid.ESI/APCI(+): 391 (M+H), 413 (M+Na); ESI/APCI(-): 389 (M-H).
19%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	A mixture of 3-phenoxybenzoic acid (0.200 g, 0.934 mmol), <strong>[942-26-7]2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride</strong> (0.215 g; 0.934 mmol), HATU (0.389 g; 1.03 mmol) and N,N-diisopropylethyldiamine (0.402 mL; 2.33 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified twice by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.068 g (19%) of the title compound as a colourless solid. [0956] ESI/APCI(+): 391 (M+H), 413 (M+Na); ESI/APCI(-): 389 (M-H).

Reference： [1]Patent: WO2012/80221,2012,A1 .Location in patent: Page/Page column 134
[2]Patent: US2013/274260,2013,A1 .Location in patent: Paragraph 0955-0956

41
[ 4545-21-5 ]
[ 3739-38-6 ]
[ 1402934-31-9 ]

Yield	Reaction Conditions	Operation in experiment
56%	With potassium carbonate In 1,4-dioxane at 110℃; for 18h; Inert atmosphere;

Reference： [1]Zhou, Ankun; Wu, Lei; Li, Dazhi; Chen, Qingqing; Zhang, Xiao; Xia, Wujiong [Chinese Journal of Chemistry, 2012, vol. 30, # 8, p. 1862 - 1866]

42
[ 3739-38-6 ]
[ 32117-52-5 ]
[ 1402934-24-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate In 1,4-dioxane at 110℃; for 18h; Inert atmosphere;

Reference： [1]Zhou, Ankun; Wu, Lei; Li, Dazhi; Chen, Qingqing; Zhang, Xiao; Xia, Wujiong [Chinese Journal of Chemistry, 2012, vol. 30, # 8, p. 1862 - 1866]

43
[ 3739-38-6 ]
[ 75230-50-1 ]
[ 1402934-34-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate In 1,4-dioxane at 110℃; for 18h; Inert atmosphere;

Reference： [1]Zhou, Ankun; Wu, Lei; Li, Dazhi; Chen, Qingqing; Zhang, Xiao; Xia, Wujiong [Chinese Journal of Chemistry, 2012, vol. 30, # 8, p. 1862 - 1866]

44
[ 3739-38-6 ]
[ 17336-66-2 ]
[ 1402934-36-4 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate In 1,4-dioxane at 110℃; for 18h; Inert atmosphere;

Reference： [1]Zhou, Ankun; Wu, Lei; Li, Dazhi; Chen, Qingqing; Zhang, Xiao; Xia, Wujiong [Chinese Journal of Chemistry, 2012, vol. 30, # 8, p. 1862 - 1866]

45
[ 3739-38-6 ]
4-methyl-N'-(1-(p-tolyl)ethylidene)benzenesulfonohydrazide [ No CAS ]
[ 1402934-37-5 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate In 1,4-dioxane at 110℃; for 18h; Inert atmosphere;

Reference： [1]Zhou, Ankun; Wu, Lei; Li, Dazhi; Chen, Qingqing; Zhang, Xiao; Xia, Wujiong [Chinese Journal of Chemistry, 2012, vol. 30, # 8, p. 1862 - 1866]

46
[ 4545-18-0 ]
[ 3739-38-6 ]
[ 1402934-38-6 ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 18h; Inert atmosphere;

Reference： [1]Zhou, Ankun; Wu, Lei; Li, Dazhi; Chen, Qingqing; Zhang, Xiao; Xia, Wujiong [Chinese Journal of Chemistry, 2012, vol. 30, # 8, p. 1862 - 1866]

47
[ 3739-38-6 ]
[ 5362-72-1 ]
[ 1402934-39-7 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate In 1,4-dioxane at 110℃; for 18h; Inert atmosphere;

Reference： [1]Zhou, Ankun; Wu, Lei; Li, Dazhi; Chen, Qingqing; Zhang, Xiao; Xia, Wujiong [Chinese Journal of Chemistry, 2012, vol. 30, # 8, p. 1862 - 1866]

48
[ 3739-38-6 ]
[ 106-45-6 ]
[ 1372783-75-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane In 1,2-dichloro-ethane at 80℃; for 20h; Inert atmosphere;

Reference： [1]Sakai, Norio; Miyazaki, Takahiro; Sakamoto, Tomohiro; Yatsuda, Takuma; Moriya, Toshimitsu; Ikeda, Reiko; Konakahara, Takeo [Organic Letters, 2012, vol. 14, # 17, p. 4366 - 4369]

49
[ 3586-14-9 ]
[ 64-19-7 ]
[ 3739-38-6 ]
[ 50789-44-1 ]
[ 39515-51-0 ]

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 416 - 424

50
[ 3082-75-5 ]
[ 3739-38-6 ]
ethyl 2-(3-phenoxybenzamido)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h;	12 4.1.1 General procedure for the preparation of compounds (10a-o) General procedure: To a suspension of various carboxylic acid 9a-o (1.0 equiv) and L-alanine ethyl ester (8, 1.0 equiv) in dichloromethane was treated with EDC (2.0 equiv). Triethylamine (1.0 equiv) was added drop wise to the mixture for a period of 30 min. After this mixture was stirred for 12 h at room temperature, it was neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane twice. The combined organic layer was dried with anhydrous Na2SO4. After Na2SO4 was filtered, solvent was removed in vacuum. The residue was purified by silica gel column chromatography with n-hexanes/ethyl acetate=1:1 to afford 10a-o as sticky oil.

Reference： [1]Cho, Joong-Heui; Jung, Kwan-Young; Jung, Younghwan; Kim, Min Hye; Ko, Hyojin; Park, Chul-Seung; Kim, Yong-Chul [European Journal of Medicinal Chemistry, 2013, vol. 70, p. 811 - 830]

51
[ 3739-38-6 ]
[ 60677-14-7 ]

Reference： [1]Russian Journal of General Chemistry,2014,vol. 84,p. 2264 - 2266
Zh. Obshch. Khim.,2014,vol. 84,p. 1906 - 1908,3

52
[ 66230-04-4 ]
[ 1745-18-2 ]
[ 622-98-0 ]
[ 1875-88-3 ]
[ 2012-74-0 ]
[ 23853-78-3 ]
[ 3739-38-6 ]
[ 938-95-4 ]
[ 39515-51-0 ]
[ 873-76-7 ]
methyl N-hydroxybenzene carboximidoate [ No CAS ]

Reference： [1]Journal of the Brazilian Chemical Society,2015,vol. 26,p. 1831 - 1837

53
[ 1111943-58-8 ]
[ 3739-38-6 ]
3-methyl-1-(3-phenoxy-benzoyl)-pyrrolidine-3-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane at 0℃; for 5h;	Intermediate 39: 3-Methyl-1-(3-phenoxy-benzoyl)-pyrrolidine-3-carboxylic acid methyl ester To a solution of 3-phenoxybenzoic acid (0.15 g, 0.70 mmol) and 3-Methyl-pyrrolidine-3-carboxylic acid methyl ester (0.1 g, 0.70 mmol) in dry dichloromethane (10 mL) was added triethylamine (0.29 mL , 2.1 mmol). The reaction cooled to 0°C and T3P (0.66 mL, 2.1 mmol) was added dropwise. The reaction was stirred for 5 h. After the completion of reaction (as evidenced by TLC), the organic layer was washed with water and purified by column chromatography to offer the titled compound as colorless liquid (87%, 0.2 g). LCMS: 340.0 (M+H), Rt. 4.6 min, 99.5 % (max), 99.5 % (254 nm).

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2015/130905, 2015, A1 Location in patent: Paragraph 00202

54
[ 920-66-1 ]
[ 3739-38-6 ]
C₁₆H₁₀F₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With diisopropyl-carbodiimide In acetonitrile for 0.166667h;	2.3 Derivatization procedure General procedure: The derivatization procedure was carried out as follows: the analytes and internal standard were dissolved in acetonitrile and mixed with HFIP, and DIC was added to start the reaction. After ten minutes, the derivatization was terminated by adding water, and 0.5mL of extraction solvent (0.5% corn oil in n-hexane) was added followed by vortex mixing. After centrifugation at 3000rpm for 5min, the supernatant was filtered through a 0.22μm filter and analyzed by GC. The derivatization reactions were shown in Fig. S1.

Reference： [1]Liu, Xueke; Shen, Zhigang; Wang, Peng; Liu, Chang; Yao, Guojun; He, Jiayuan; Liu, Donghui; Zhou, Zhiqiang [Food Chemistry, 2016, vol. 196, p. 828 - 832]

55
[ 3739-38-6 ]
[ 74-88-4 ]
[ 93533-84-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 3-phenoxybenzoic acid With tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate; copper(II) acetate monohydrate; potassium carbonate; trimethylpyruvic acid In N,N-dimethyl-formamide at 140℃; for 7h; Inert atmosphere; Stage #2: methyl iodide With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;	Rh-Catalyzed Reaction of 3-Phenoxybenzoic Acid (entry 13 in Table 1) A mixture of3-phenoxybenzoic acid (1a) (0.25 mmol, 54 mg), [Cp*Rh(MeCN)3][SbF6]2 (0.01 mmol, 8.3 mg),Cu(OAc)2·H2O (0.5 mmol, 100 mg), pivalic acid (0.25 mmol 26 mg), K2CO3 (0.25 mmol, 35 mg),and dibenzyl (ca. 30 mg) as internal standard was stirred in DMF (2 mL) under nitrogen at 140 oC for7 h. After cooling, CH3I (1.5 mmol) and K2CO3 (0.75 mmol, 104 mg) were added and the resultingmixture was stirred under air at room temperature for 12 h. Then the reaction mixture was diluted byethyl acetate (100 mL). The organic layer was washed by water (100 mL, three times) and dried overNa2SO4. After evaporation of the solvent under vacuum, product 2a was isolated by columnchromatography on silica gel using hexane-ethyl acetate (80:1, v/v) as eluant.

Reference： [1]Okada, Takeshi; Unoh, Yuto; Satoh, Tetsuya; Miura, Masahiro [Chemistry Letters, 2015, vol. 44, # 11, p. 1598 - 1600]

56
[ 3739-38-6 ]
[ 74-88-4 ]
C₁₃H₇⁽²⁾H₃O₃ [ No CAS ]
dibenzo[b,d]furan-1-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 55% 2: 8%	Stage #1: 3-phenoxybenzoic acid With tetradeuterioacetic acid; tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate; copper(II) acetate monohydrate; potassium carbonate In N,N-dimethyl-formamide at 140℃; for 5h; Inert atmosphere; Stage #2: methyl iodide With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;	Reaction of 1a in the Presence of CD3CO2D (Scheme 3) A mixture of 3-phenoxybenzoicacid (1a) (0.25 mmol, 54 mg), [RhCl(cod)]2 (0.005 mmol, 2.5 mg), Cu(OAc)2·H2O (0.5 mmol, 100mg), CD3CO2D (0.25 mmol 16 mg), K2CO3 (0.25 mmol, 35 mg), and dibenzyl (ca. 30 mg) asinternal standard was stirred in DMF (2 mL) under nitrogen at 140 oC for 5 h. After cooling, CH3I(1.5 mmol) and K2CO3 (0.75 mmol, 104 mg) were added and the resulting mixture was stirred underair at room temperature for 12 h. Then the reaction mixture was diluted by ethyl acetate (100 mL).The organic layer was washed by water (100 mL, three times) and dried over Na2SO4. AfterS-2evaporation of the solvent under vacuum, product 2a as well as recovered 1a were isolated bycolumn chromatography on silica gel using hexane-ethyl acetate

Reference： [1]Okada, Takeshi; Unoh, Yuto; Satoh, Tetsuya; Miura, Masahiro [Chemistry Letters, 2015, vol. 44, # 11, p. 1598 - 1600]

57
[ 3739-38-6 ]
[ 693-13-0 ]
N,N'-diisopropyl-N-(3-phenoxybenzoyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	In water at 20℃; for 1h; Green chemistry;	2.1 General Procedure for the Preparation of Compounds (9,12) General procedure: To a magnetically stirred solution of carboxylic acid (1 mmol) in H2O was added 1 mmol of carbodiimide 2. After total consumption of starting material (TLC monitoring), the organic solvent was evaporated under reduced pressure and the viscous residue was purified by preparative layer chromatography (PLC) (silica gel (F254) powder; petroleum ether-ethyl acetate (4:1)). The characterization data of the compounds are given below. 2.1f N,N-Diisopropyl-N-(3-phenoxybenzoyl)urea (9f): Yellow powder, (yield: 92%), M.p. 152-154 °C. IR(KBr): v=3351 (NH), 3073, 2979, 1685, 1638, 1582,1248, 758 cm-1.1H NMR (250 MHz, CDCl3)δ(ppm):1.02 (d, 6H, J=6.5 Hz, CH3 isopropyl); 1.39 (d, 6H,J=6.7 Hz, CH3isopropyl); 3.78-3.95 (m, 1H, CH isopropyl); 4.25-4.41 (m, 1H, CH isopropyl); 6.99 (broaddoublet, 1H, NH); 7.02-7.47 (m, 9H, CHarom).13CNMR(62.5 MHz, CDCl3)δ(ppm): 20.8, 22.3 (4CH3,isopropyl); 42.7, 50.6 (2CH, isopropyl); 116.0, 119.4,120.4, 120.6, 124.1, 129.1, 130.2 (9CH, arom); 138.7,153.8, 156.2 (3C, arom); 157.8, 171.8 (2C=O). Analysis of C20H24N2O3 (340.42). (% calculation/ found): C:70.56/70.61, H: 7.11/7.17, N: 8.23/8.18.

Reference： [1]Ramazani, Ali; Nasrabadi, Fatemeh Zeinali; Rezaei, Aram; Rouhani, Morteza; Ahankar, Hamideh; Asiabi, Pegah Azimzadeh; Joo, Sang Woo; ͆lepokura, Katarzyna; Lis, Tadeusz [Journal of Chemical Sciences, 2015, vol. 127, # 12, p. 2269 - 2282]

58
[ 3739-38-6 ]
[ 73874-95-0 ]
tert-butyl (1-(3-phenoxybenzoyl)piperidin-4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane for 15h;	67.A Step A. Preparation of tert-butyl (l-(3-phenoxybenzoyl)piperidin-4-yl)carbamate To a stirred solution of EDC (0.292 mmol), ΗΟΒΤ (0.0474 mmol), 3- phenoxybenzoic acid (0.233 mmol) in DCM (0.1M) and TEA (0.934 mmol) was added tert- butyl piperidin-4-ylcarbamate (0.257 mmol). The reaction mixture was stirred for 15 h then concentrated in vacuo. The residue was purified by flash column chromatography (Combi- Flash Rf, Hex/EtOAc 0-70% gradient) yield the title compound as a white solid.

Reference： [1]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2015/148854, 2015, A1 Location in patent: Paragraph 00498

59
[ 3739-38-6 ]
[ 40872-87-5 ]
C₂₁H₁₆ClNO₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 2423 - 2435

60
[ 3739-38-6 ]
[ 593-56-6 ]
C₁₄H₁₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 3-phenoxybenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3.5h; Stage #2: N-methoxylamine hydrochloride With potassium carbonate In water; ethyl acetate at 20℃; for 20h;

Reference： [1]Dai, Huimin; Yu, Chao; Wang, Zihao; Yan, Hong; Lu, Changsheng [Organic Letters, 2016, vol. 18, # 14, p. 3410 - 3413]

61
[ 3739-38-6 ]
[ 134461-75-9 ]
N6-(3-phenoxybenzoyl)adenine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl acetamide at 100 - 130℃;	General Synthetic Procedure for N6-Benzoyladenine Derivatives General procedure: Benzoic acid (1.0 eq) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.2 eq) were added to a suspension of adenine (1.0 eq) in anhydrous N-dimethylacetamide (DMA), and the mixture was stirred at 100-130°C. After completion of the reaction, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (MeOH-CHCl3) and by washing with AcOEt and/or CH2Cl2-hexane (1 : 1 or 1 : 0) to afford the product.

Reference： [1]Amemiya, Seika; Yamaguchi, Takao; Sakai, Taki; Hashimoto, Yuichi; Noguchi-Yachide, Tomomi [Chemical and Pharmaceutical Bulletin, 2016, vol. 64, # 9, p. 1378 - 1383]

62
[ 95-14-7 ]
[ 3739-38-6 ]
(1H-benzo[d][1,2,3]triazol-1-yl)(3-phenoxyphenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 3-phenoxybenzoic acid With thionyl chloride In dichloromethane at 0 - 5℃; for 0.25h; Stage #2: 1,2,3-Benzotriazole In dichloromethane at 35℃;
78%	Stage #1: 3-phenoxybenzoic acid With trichloroisocyanuric acid; triphenylphosphine In dichloromethane at 20℃; for 0.5h; Stage #2: 1,2,3-Benzotriazole In dichloromethane at 20℃;	(1H-1,2,3-Benzo[d][1,2,3]triazol-1-yl)(phenyl)methanone (2a); Typical Procedure General procedure: Trichloroisocyanuric acid (0.640 g, 2.76 mmol, 0.35 equiv) and PPh3 (0.640 g, 2.76 mmol, 1.2 equiv) were taken in anhyd DCM in a round-bottomed flask. After stirring for 10 min, benzoic acid (1a; 0.962 g, 7.89 mmol, 1.0 equiv) was added and the reaction mixture was stirred for an additional 30 min. Then, benzoic acid (0.939 g, 7.89 mmol, 1.0 equiv) was added and the resulting mixture was allowed to stir for 4-5 h. After completion of the reaction (monitored by TLC), the reaction mass was concentrated under reduced pressure until dry. Purification using flash column chromatography (SiO2) using gradient mixtures of EtOAc and n-hexane gave 2a in pure form; white solid; yield: 1.62 g (92%, 7.29 mmol) mp 111-114 °C; Rf = 0.6 (5% EtOAc/n-hexane).

Reference： [1]Singh, Anoop S.; Kumar, Dhananjay; Mishra, Nidhi; Tiwari, Vinod K. [RSC Advances, 2016, vol. 6, # 87, p. 84512 - 84522]
[2]Singh, Mala; Singh, Anoop S.; Mishra, Nidhi; Agrahari, Anand K.; Tiwari, Vinod K. [Synthesis, 2019, vol. 51, # 10, p. 2183 - 2190]

63
[ 64-17-5 ]
[ 3739-38-6 ]
[ 60677-14-7 ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 7760 - 7770

64
[ 3739-38-6 ]
3-((benzyloxy)methyl)-5-methyl-1-(piperidin-3-yl)pyrimidine-2,4(1H,3H)-dione [ No CAS ]
C₃₁H₃₁N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere;	4 4.4.4. 5-Methyl-1-(1-(3-phenoxybenzoyl)piperidin-3-yl)pyrimidine-2,4(1H,3H)-dione (13) To the reaction mixture of 3-((benzyloxy)methyl)-5-methyl-1-(piperidin-3-yl)pyrimidine-2,4(1H,3H)-dione (34, 132.75 mg, 0.403 mmol) and 3-phenoxybenzoic acid (129.49 mg, 0.605 mmol) in dry CH2Cl2 (10 mL) was added EDC (125.12 mg, 0.806 mmol) and 4-DMAP (1.32 mg) at room temperature under argon. The reaction mixture was stirred overnight, diluted with CH2Cl2 (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified with column chromatography (ethyl acetate/hexane, 25 → 65% in a linear gradient elution). The resulting amide intermediate was dissolved in EtOH (10 mL) and Pd/C (0.15 g) was added. The reaction was stirred under hydrogen for 6 h and the suspension was filtered. The filtrate was evaporated and dried under high vacuum for 0.5 h. The residue was dissolved in a mixture of THF/H2O (10 mL, v/v = 2/1) and stirred for 4 h. After evaporation, the residue was purified with column chromatography (MeOH/CH2Cl2, 1 → 10% in linear gradient elution). After lyophilization, the desired product was obtained as a white powder (131.10 mg, 80.2%). 1H NMR (300 MHz, DMSO-d6, 80 °C) δ: 1.46-1.65 (m, 1H, piperidin-5a-yl), 1.74-2.08 (m, 6H, 5-CH3, piperidin-4-yl, piperidin-5b-yl), 2.91 (t, J = 11.72 Hz, 1H, piperidin-6a-yl), 3.15 (t, J = 11.86 Hz, 1H, piperidin-2a-yl), 3.80-4.21 (m, 2H, piperidin-2b-yl, piperidin-6b-yl), 4.33 (tt, J = 11.31, 4.36 Hz, 1H, piperidin-3-yl), 6.99 (dd, J = 2.34, 1.46 Hz, 1 H) 7.03-7.11 (m, 3 H) 7.13-7.20 (m, 2 H) 7.37-7.48 (m, 3 H) 7.52 (d, J = 1.17 Hz, 1 H) 10.95 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6) δ: 12.12 (5-CH3), 24.96 (piperidin-5-yl), 28.21 (piperidin-4-yl), 52.08 (piperidin-3-yl), 109.04 (C-5), 116.50 (Ph), 119.10 (2C, Ph), 119.39 (Ph), 121.46 (Ph), 123.93 (Ph), 130.16 (2C, Ph), 130.27 (Ph), 137.51 (C-6), 137.67 (Ph), 150.72 (C-2), 156.08 (Ph), 156.85 (Ph), 163.59 (C-4), 168.32 (CO, benzoyl). C (piperidin-2-yl) and C (piperidin-6-yl) cannot be found. HRMS (ESI): calculated for [C23H23N3O4+H]+, 406.1761; found, 406.1775.

Reference： [1]Song, Lijun; Risseeuw, Martijn D.P.; Froeyen, Matheus; Karalic, Izet; Goeman, Jan; Cappoen, Davie; Van der Eycken, Johan; Cos, Paul; Munier-Lehmann, Hélène; Van Calenbergh, Serge [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5172 - 5182]

65
[ 3739-38-6 ]
(R)-N-(aminomethyl)-3-(N-(benzyloxy)formamido)-2-(cyclopentylmethyl)propanamide [ No CAS ]
(R)-N-((3-(N-(benzyloxy)formamido)-2-(cyclopentylmethyl)propanamido)methyl)-3-phenoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 18h;	INTERMEDIATE 84(R)-N-((3-(N-(benzyloxy)formamido)-2-(cyclopentylmethyl) propanamido)methyl)-3-phenoxybenzamide A solution of EDO (423 mg, 2.20 mmol), (R)-N-(aminomethyl)-3-(N-(benzyloxy)formamido)-2-(cyclopentyl methyl)propanamide (245 mg, 0.74 mmol), HOBt (22.5mg, 0.15 mmol), 3-phenoxybenzoic acid (189 mg, 0.88 mmol) and DIPEA (0.64 ml, 3.67mmol) in DMF (5 ml) and THF (5 ml) was stirred at room temperature for 18 hours. Thereaction was then diluted by the addition of NH4CI and EtOAc. The mixture was extractedwith EtOAc (3 x) and the combined organic layers were washed with brine (2 x), dried overNa2504, filtered and concentrated. The residue was purified by flash chromatography (ISCO,120 g silica column, 65 mI/mm, 0-60 % EtOAc/DCM over 45 minutes) to give the title product (380 mg, 98 % yield). MS (m/z) 530.3 (M+H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2017/6295, 2017, A1 Location in patent: Page/Page column 137; 138

66
[ 3739-38-6 ]
[ 5720-05-8 ]
3'-Phenoxy-4-methylbenzophenon [ No CAS ]